An extinction-based therapy (EBT) in which smokers smoke denicotinized (`denic') cigarettes and wear a nicotine patch in the weeks leading up to a target quit date has shown promise as a novel and effective treatment for nicotine dependence. This EBT pretreatment (EBT-PRE) breaks the contingent relationship between smoking a cigarette and nicotine delivery, thus promoting extinction of smoking behavior and making it easier for the smoker to quit. EBT-PRE has a potential advantage over clinic- based EBTs in that extinction training can occur in a wide variety of contexts (i.e. in all of the contexts the smoker typically smokes). Therefore, it may not be as susceptible to the `renewal effect' in which extinction in one context does not generalize to others. Recent clinical trials of EBT-PREs using denics plus the nicotine patch have reported 4 week continuous abstinence rates in the 30 to 50% range. In a recent study, we observed EBT-PRE to attenuate brain reactivity to smoking-related cues in the amygdala-a critical substrate of reward learning and extinction. The overarching goal of the present application is to further elucidate the neural basis of EBT-PRE. One hundred (n=100) smokers will be randomly assigned to one of two treatment arms: an extinction-based therapy (EBT; n=50) arm in which participants will smoke denic cigarettes while wearing a 21 mg/d nicotine patch for one month prior to their quit date or a nicotine replacement therapy (NRT; n=50) arm in which participants will smoke their usual brand of cigarettes up to the quit date. Following the quit date, both groups will undergo standard nicotine replacement therapy. Overlaid on this randomized trial, brain cue-reactivity (CR) will be measured using fMRI at baseline [fMRI71], in the fourth week of the pretreatment period [fMRI72] and within 24 hrs of quitting smoking [fMRI73]. We hypothesize that EBT will result in decreased amygdalar reactivity to smoking-related cues compared to NRT and that greater brain CR at baseline (and greater attenuation of brain CR by EBT) will be associated with better EBT outcomes. This project builds upon the investigative team's earlier work and expertise and is highly responsive to the RFA which seeks research that elucidates the `mechanisms of extinction that might guide interventions' and `identifies brain mechanisms...involved in extinction'. EBT-PRE represents a novel, potentially effective and highly disseminable treatment for nicotine dependence and elucidating the neural mechanisms underlying it will lead to further refinement of this therapy. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading preventable cause of death and disability in the U.S. A new smoking cessation treatment seeks to break the relationship between smoking a cigarette and delivery of nicotine to the brain making it easier for smokers to quit. Clinical trials of this `extinction-based' therapy (EBT) suggest it is safe and potentially effective; however, little is known about how it changes brain function. The proposed research will lead to a better understanding of the neural basis of EBT which will lead to further refinement of this promising new treatment.